Wall-sealing treatment for minute capsules and minute capsules having walls of sealed polymeric material

ABSTRACT

A method is provided for treating preformed, solvent-swollen, capsule walls, en masse, with an organic solvent solution of waxy material. The capsule walls, on being subsequently dried, retain an amount of the treatment material which serves to modify physical characteristics of the capsule wall by providing a degree of hydrophobicity thereto.

United States Patent Inventor Appl. No. Filed Patented AssigneeWALL-SEALING TREATMENT FOR MINUTE CAPSULES AND MINUTE CAPSULES HAVINGWALLS 0F SEALED POLYMERIC MATERIAL 13 Claims, No Drawings US. Cl252/316, 117/100 A, 117/100 B, 424/33, 424/35, 424/38. 424/230, 424/324,424/330 Int. Cl B0lj 13/02,

[50] Field of Search 252/316; 117/100 0, 63; 167/82-83 DF; 264/341;424/35, 38

[56] References Cited UNITED STATES PATENTS 3,155,590 11/1964 Miller etal. 167/83 FOREIGN PATENTS 956,300 4/1964 Great Britain 117/100 0Primary Examiner-Richard D. Lovering Allorneys- Louis A. Kline andJustin S. Compton ABSTRACT: A method is provided for treating preformed,solvent-swollen, capsule walls, en masse, with an organic solventsolution of waxy material. The capsule walls, on being subsequentlydried, retain an amount of the treatment materi al which serves tomodify physical characteristics of the capsule wall by providing adegree of hydrophobicity thereto.

WALL-SEALING TREATMENT FOR MINUTE CAPSULES AND MINUTE CAPSULES HAVINGWALLS F SEALED POLYMERIC MATERIAL This invention relates to a method forsealing the polymeric material walls of minute capsules by treating suchcapsules with waxy material, en masse, while the walls are swollen byimbibed solvent. It more specifically pertains to the treatment of thecapsule wall material with the aim of (a) controlling the release rateof the capsule contents by liquid-leaching action through the capsulewall, (b) preserving the stability of watersensitive capsule contentsunder high relative humidity storage conditions, and (c) adjusting therelease rate of capsule contents through the walls in elevatedenvironmental liquid media temperatures.

in the art of producing minute capsules which contain water-sensitivematerials, the use of hydrophobic polymeric wall materials, such asethyl cellulose, is well known. In encapsulating procedures such asthose discussed in U.S. Pat. No. 3,l55,590, which issued Nov. 3, I964,on the application of Robert E. Miller and Jerrold L. Anderson, thehydrophobic film-forming materials are dissolved in an organic solventin which the intended capsule contents is dispersed as particles, and asecond polymeric material is added, which serves to act as a phaseseparation inducer. At a warm manufacturing temperature of less than 80C., the hydrophobic film-fonning material separates as liquidpolymer-rich globules from the manufacturing medium, and deposits on,and forms embryonic seamless liquid walls about, each individualparticle as a capsule core entity. This leaves the solvent-poor wallsand contents in a solvent-rich equilibrium liquid. Because the phaseseparation of polymeric materials from a liquid system is an equilibriumprocess, an amount of the phase-separationinducing polymeric materialcan be found in both the solventrich phase and the solvent-poor phase ofthe encapsulation system.

In a first form of the invention, once the capsules are formed with thesolvent-swollen walls and an equilibrium is reached in the system, thereis introduced into the system a solution of a waxy material in the samekind of solvent as that used in the system. In reaching a newequilibrium, the waxy material is distributed by diffusion into thesolvent in the wall material according to the concentration gradient inexistence across the interface between the external phase and thecapsule wall phase. Upon the solvents being eliminated from the capsulewalls by drying, the wax is left as a residue in the walls. The capsulewalls, in shrinking on solvent loss, entrap the wax tightly as a sealingmaterial.

In another form of the invention, the untreated capsules are recoveredfrom the manufacturing system in dried form and then redispersed in asolution of a wall-swelling solvent and a wax, to achieve the same waxpenetration of the wall by ab sorption to a point where substantialequilibrium is reached. The capsules are then dried, as in the firstform of the invention. The drying may be by any mode of eliminatingsolvent.

The establishment of the equilibrium state, wherein the waxy material iscarried into the walls, may take several minutes, as the diffusion ratethrough the wall material is slow.

Sealing materials which can be utilized in the practice of thisinvention include natural and synthetic waxes which are soluble insolvents otherwise eligible for such capsule wall treatment. Eligibilityof a solvent is decided by its ability to swell but not dissolve capsulewalls at the process temperature. in that respect, an eligible solventis one which is a poor solvent for the wall material. Waxes which havebeen applied to the practice of this invention include paraffin wax,beeswax, glycerol tristearate, microcrystalline wax,polyethylene-polyvinylacetate copolymer, and combinations of the above.The preferred treatment material is paraffin wax, but other, equivalent,materials can be used with success, the only requirement being thatwhich was previously stated-that property of adequate solubility in themanufacturing vehicle solvent.

While the preferred embodiment of this invention utilizes capsule wallmaterials which are substantially ethyl cellulose,

other polymeric film-forming materials, such as polyvinyl pyrrolidone,polyvinyl pyrrolidone-vinyl acetate copolymers, or vinyl chloride-vinylacetate copolymers, can be used. Capsules prepared by the techniques andwith the materials described in U.S. Pat. No. 3,34l,4l6 issued Sept. I2,1967 on the application of Jerrold L. Anderson, Gary L. Gardner, andNoble H. Yoshida and in the previously mentioned U.S. Pat. No. 3,155,590can be treated by this invention, provided that they are in asolvent-swollen condition in an eligible solvent, which is notnecessarily the solvent in which they were manufactured.

The contents of capsules to be treated by the novel method generally areunimportant, because the treatment affects only the capsule walls unlessthe contents happens to be soluble in the treatment solvent or reactivetherewith. A few of the materials which have been included as corematerials in the treated capsules as aspirin, N-acetyl-p-aminophenol,phenylephrine hydrochloride, amphetamine sulfate, chlorpheniraminemaleate, meprobamate, spiramycin, oxytetracycline hydrochloride,potassium penicillin G, sodium fiuorescein, sodium bicarbonate,potassium chloride, and ammonium dichromate.

In the above discussion, this invention has been defined in generalterms. Preferred and other specific embodiments of the invention willnow be described. The examples of both materials and process techniquesshould be considered illustrative of, and not limiting, the practice ofthe invention, as it will be seen that unspecified variations in theexamples of the invention do not detract from the spirit of theinvention.

EXAMPLE 1 Preferred Embodiment In the encapsulation ofN-acetyl-p-aminophenol (APAP), the following materials were placed in ajacketed vessel equipped for agitation:

5,000 g. cyclohexane g. polyethylene, as later specified I00 g. ethylcellulose, as later specified 500 g. APAP (250-micron particle size) Thepolyethylene used was low-viscosity material having a molecular weightof approximately 7,000 and a ring and ball softening point of 100 to l0lC. as determined according to the American Society for Testing MaterialsSpecification D-36-26 (Epolene C-lO" as sold by Eastman ChemicalProducts, Kingsport, Tenn. United States of America). The ethylcellulose material had an ethoxyl content of 48.0 percent to 49.5percent, by weight, and a viscosity, at 25 C., of 90 to centipoises asmeasured by an Ubbelohde viscometer in a 5 percent, by weight, solutionof the ethyl cellulose in a solvent mixture of 80-20 toluene-ethanol.

Agitation was initiated sufficient to keep the APAP particles insuspension, and the vessel contents were heated. When 80 C. wasattained, the heat source was removed, and the agitating system wasallowed to cool to 35 C. Agitation then was stopped, and, after thenow-encapsulated core particles were allowed to settle as a capsulemass, the cyclohexane manufacturing solvent was decanted. The capsuleswere washed by adding 2,500 g. of pure cyclohexane to thecapsulecontaining vessel and agitating the system for about 15 minutesor slightly longer. The capsules were again allowed to settle, and thecyclohexane was decanted. Two further washes were performed in the samemanner. After washing was completed, the remaining capsule slurry wasfiltered to a cake and dried, by evaporation of the solvent, to formparticulate capsules.

One hundred g. of the so-prepared dried capsules was dispersed in 500 g.of a 20 percent, by weight, cyclohexane solution of paraffin wax, whichis a purified mixture of solid petroleum hydrocarbons having a meltingpoint range of 43 to 66 C., depending on the grade of wax used. Themixture was agitated at about room temperature for about one-half houror slightly less. after which time the treated capsules were separatedfrom the wax-containing solvent system by filtration and were dried bycirculated air maintained at about 25 C. As a test, samples of thetreated (a) and the untreated (b) APAP- step in the process of preparingthe capsules for recovery from the manufacturing liquid. First-hour testresults were 12.6 percent of the total APAP released from the treatedcapsules and 43.0 percent of the total APAP released from the untreatedcontaining capsules were evaluated as to release by a leaching 5capsules in an aqueous, 1.2 pH-buffered, solution maintained actioninduced through the capsule wall at 37 C. in an aqueat 37C. ous systembuffered at l.2 pH (simulated gastric environment). The following tableshows results of that test in terms EXAMPLE 4 f the pefcehtage of totalcore material released at Specified l0 Phenylephrine hydrochloride, ascore material, was encapthhes dunhg the testsulated by the sametechnique as in example I. To prepare the intended core material forencapsulation, it was intimately Ummtcd combined with an amount ofpercent, by weight, aqueous gum arabic solution sufficient to yield adoughy consistency. i; 2:; 5 This mass was then passed through a wetgranulator to granu- 7 8% 3 48.1% 850% late it, dried, and the productsieved. Two hundred g. of the 4 56.9% granulated material having anaverage granule size of 590 to 5 640% 840 microns were substituted forthe APAP in the encapsulation formula of example l. After encapsulation,one portion f It is readily seen that the treated capsules released theof [he capsules was treated using paraffin wax and a APAP much mol'eSlowly than did the untreated capsules in second portion g was treatedusing glycerol tristearate accordthe same simulated gastric environment,which was the object i to h hi f hi i i Th two ki d of to beachievedtreated capsules, f and g, were tested against nontreated cap-The foregoing is an example of the invention carried sules h in anaqueous, l.2 pH-bufiered solution maintained at after removal of thecapsules from the manufacturing vehicle. 37 The f ll i table Showsresults f h test i terms f percentage of total core material released ata specified time EXAMPLE 2 during the test. In this example, capsuleswere prepared by the same technique as in example I with the exceptionthat 900 g. of Hours acetylsalicylic acid (aspirin) having an averageparticle size of Pammn' less than 840 microns was substituted for theAPAP of that exnamed swumeammd ample. As an example of the ability tovary capsule release characteristics by the use of different waxes, twotreatments 06 205% 45 m were performed on separate dried capsule samplesfrom this 0 200g, 38 1; q encapsulation batch. The first treatment,sample c, utilized the 1 5 70 5'1 paraffin wax of example I. and thesecond treatment, sample 57 75 d, utilized a wax combination of 80percent, by weight, paraf- 1 g fin and 20 percent, by weight,polyethylene-polyvinyl acetate copolymer having 27 percent to 29percent, by weight, vinyl 40 acetate content and a number averagemolecular weight of EXAMPLES 240,000 ("Elvax 250", as sold by E. lvduPont deNemours and Company, Incorporated, Wilmington, Del., UnitedStates of Amphetamine phoephate was granulated accordmg to the America).In each of the treatments 0 and d, the technique was techhlque of theprhwous example ahd 600 of the grhhules Similar to that in example 1except for the type of wax AS a having an average slze of 420 to 840microns was substituted test of release characteristics, samples of cparafiin-treated for the APAP h the ehchpshlahoh formula of examplecapsules, d wax mixture-treated capsules, and e untreated cap- Afterehcapshlahoh one pomoh of the capsules e treated sules were evaluatedseparately in identical aqueous systems as before h paraffih h releaseCharactehshcs of buffered at 7.4 pH and kept at 37 C. to simulate oneenteric wah'hpeated and Untreated 1 ciapsules were compared atenvironment. The following table shows results of that test in anaqueous system whlch the buffered PH h vaned terms of the percentage ofthe total capsule-content material from t l hour) to (at 6 hours) h toShhuhhe 3 released at Specified times during tha ESL gastrointestinalenvironment. The following table shows the test results in terms ofpercentage of total capsule content Hum released at a specified timeduring the test:

(C) Parulfin 1d) Puruffin-colL'l Untreated llfl v polymcblrvuwd Hours inTreated l1) Untreated l U'l I h; 1 61 I l2 5% lib 3; 2 l4; 4 w, n .1 7.2 w 3% 92 0a 1 l w; n 2'; u m 0 4 30 7'1 4 2.5; K I llU'l (v 42.1% 5 3 0q m ism Although specific amounts and concentrations of materials Fromthe above datait is pp that release charac' have been recommended, itmust be understood, as obvious, teristies eah be Varied by the type ofwax or mixture of waxes 5 that the nature of the novel wax treatmentallows numerous e h the treatment of the eapsules' untreated capsulesbeing variations within the implications of the invention. Thewaxrelease rate' solvent system is optimum in most cases, at about 20percent,

EXAMPLE 3 by weight, wax, but it functions properly at any lower waxconcentratron-the effect of the treatment only being decreased In thisexample, capsules containing APAP were prepared accordingly in degree.At wax concentrations above the opand treated as in example I with theexception that a portion timum, there is a tendency for excess wax toremain undisof the capsules were wax-treated during the thirdcyclohexane solved and to cover the capsule walls in the form ofawax-parwash rather than washed, dried, and then redispersed for waxticle coating. Such a second coating should be used guardedly,treatment. Wax concentration in the third wash solvent was 20 as itincreases manufacturing and processing costs and alters percent, byweight. In this case, the wax treatment became a the releasecharacteristics of the capsules, which may or may not be desirable. Theprocess soaking" time which has been suggested in the examplesrepresents only a practical operating time. The treatment involvesestablishment of an equilibrium of solvent solutions, that within thecapsule wall material being impeded in mobility. In some cases,equilibrium may be substantially established in 5 minutes or less, and,in other cases, it might require a matter of hours, depending, again,upon the kind of wax used for treatment and its concentration, and uponthe condition of the wall material. The temperature of the treatmentsolutions in these examples was about to C., unless otherwise noted, butthe treatment can be carried on at any temperature within a range which,at its lowest, is that at which the treatment wax just remains insolution up to, at the highest, the temperature at which the solvent orthe environment begins to degrade the capsule wall material.

It should now be understood that there are several things which must beadjusted to cooperate in the practice of this invention, none of whichneed be exactly specified but all of which can be easily determinedempirically by one skilled in the art. In general, the wax is carriedinto the wall material, where it stays, locked in by shrinkage of thepolymeric material of the wall on drying.

What is claimed is:

l. A process for treating organic liquid-swollen polymeric film-formingmaterial composing the walls of minute capsules to render them sealedagainst liquid diffusion extraction of the capsule contents, whichincludes the steps of a. dispersing the minute capsules in an organicliquid capable of swelling but not dissolving the capsule walls, saidorganic liquid having dissolved in it a wax which, in such solutionstate, permeates the swollen capsule walls,

b. separating the wax solution-permeated capsules from the residualwax-containing liquid, and

c. removing the liquid from the capsule walls.

2. The process of claim 1 wherein the capsule walls consistsubstantially of ethyl cellulose polymeric material.

3. The process of claim 2 wherein the liquid is substantiallycyclohexane.

4. The process of claim 3 wherein the wax is substantially paraffin wax.

5. A process for treating, in the latter stages of en masse capsulemanufacture carried on in a liquid vehicle, solventswollen polymericmaterial composing the walls of capsules, said process including thesteps of a. establishing a slurry by dispersing the capsules havingsolvent-swollen walls in a liquid solvent-miscible solution of wax, saidsolution penetrating the swollen capsule walls,

b. separating the capsules from the wax-containing liquid that is freeafter substantial solution equilibrium has been attained, and

c. removing the residual liquid from the capsule walls.

6. The process of claim 5 wherein the capsule walls consistsubstantially of ethyl cellulose polymeric material.

7. The process of claim 6 wherein the liquid is substantiallycyclohexane.

8. The process of claim 7 in which the wax is substantially paraffinwax.

9. A minute capsule having, as a wall, hydrophobic polymeric material,which material has been permeated throughout with a waxy material.

10. The capsule of claim 9 wherein the hydrophobic wall material isethyl cellulose polymeric material.

11. The capsule of claim 9 wherein the waxy material is substantiallyparaffin wax.

12. A process of treating ethyl cellulose-walled capsules to seal thewalls to penetration by a leaching liquid, comprising the steps of a.soaking the capsules in a solution of waxy material in a solvent thatswells the ethyl cellulose walls for a time until an equilibrium hasbeen attained; and

b. recovering the capsules from said solution and drying them ofsolvent, leaving the wax in the walls, which walls,

by consequent shrinking, hold the wax as in a matrix. 13. A method forimpregnating the polymeric film-forming material walls of capsules witha waxy sealing material, including the steps of a. soaking the capsulesin an organic liquid solution of the waxy material, the solvent of whichsolution swells but does not dissolve the polymeric film-formingmaterial, said soaking being continued until a substantial diffusionequilibrium is attained, and b. removing the capsules from the solutionand the organic solvent from the capsule walls, leaving the waxymaterial as a residuum.

2. The process of claim 1 wherein the capsule walls consistsubstantially of ethyl cellulose polymeric material.
 3. The process ofclaim 2 wherein the liquid is substantially cyclohexane.
 4. The processof claim 3 wherein the wax is substantially paraffin wax.
 5. A processfor treating, in the latter stages of en masse capsule manufacturecarried on in a liquid vehicle, solveNt-swollen polymeric materialcomposing the walls of capsules, said process including the steps of a.establishing a slurry by dispersing the capsules having solvent-swollenwalls in a liquid solvent-miscible solution of wax, said solutionpenetrating the swollen capsule walls, b. separating the capsules fromthe wax-containing liquid that is free after substantial solutionequilibrium has been attained, and c. removing the residual liquid fromthe capsule walls.
 6. The process of claim 5 wherein the capsule wallsconsist substantially of ethyl cellulose polymeric material.
 7. Theprocess of claim 6 wherein the liquid is substantially cyclohexane. 8.The process of claim 7 in which the wax is substantially paraffin wax.9. A minute capsule having, as a wall, hydrophobic polymeric material,which material has been permeated throughout with a waxy material. 10.The capsule of claim 9 wherein the hydrophobic wall material is ethylcellulose polymeric material.
 11. The capsule of claim 9 wherein thewaxy material is substantially paraffin wax.
 12. A process of treatingethyl cellulose-walled capsules to seal the walls to penetration by aleaching liquid, comprising the steps of a. soaking the capsules in asolution of waxy material in a solvent that swells the ethyl cellulosewalls for a time until an equilibrium has been attained; and b.recovering the capsules from said solution and drying them of solvent,leaving the wax in the walls, which walls, by consequent shrinking, holdthe wax as in a matrix.
 13. A method for impregnating the polymericfilm-forming material walls of capsules with a waxy sealing material,including the steps of a. soaking the capsules in an organic liquidsolution of the waxy material, the solvent of which solution swells butdoes not dissolve the polymeric film-forming material, said soakingbeing continued until a substantial diffusion equilibrium is attained,and b. removing the capsules from the solution and the organic solventfrom the capsule walls, leaving the waxy material as a residuum.